JP2022510439A - New pharmaceutical product - Google Patents

Abstract

(E) -1- (4- (5-Carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazole -1-yl) Buta-2-en-1-yl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [d] imidazole-5- A novel pharmaceutical formulation containing carboxamide, a method of producing it, and a method of using it are disclosed. [Selection diagram] None

Description

により表され、以下、化合物Aと称される、(E)-1-(4-(5-カルバモイル-2-(1-エチル-3-メチル-1H-ピラゾール-5-カルボキサミド)-7-(3-モルホリノプロポキシ)-1H-ベンゾ[d]イミダゾール-1-イル)ブタ-2-エン-1-イル)-2-(1-エチル-3-メチル-1H-ピラゾール-5-カルボキサミド)-7-メトキシ-1H-ベンゾ[d]イミダゾール-5-カルボキサミド、
又はその互変異性体、
又はその薬学的に許容される塩
を含む、製剤、及び注射用剤形を製造する方法に関する。 The present invention has the following structure:

Represented by, hereinafter referred to as Compound A, (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7- ( 3-Morholinopropoxy) -1H-benzo [d] imidazole-1-yl) buta-2-en-1-yl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7 -Methyl-1H-benzo [d] imidazole-5-carboxamide,
Or its tautomer,
Or a method for producing a pharmaceutical product and an injectable dosage form containing a pharmaceutically acceptable salt thereof.

The present invention particularly relates to a method for producing an aqueous, powder or lyophilized pharmaceutical formulation. Aqueous formulations are ready for injection, while powders and lyophilized formulations require reconstitution in a suitable medium prior to administration.

(E) -1- (4- (5-Carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazole -1-yl) Buta-2-en-1-yl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [d] imidazole-5- Carboxamide is a transmembrane protein that is also known as STING (Stimulator of Interferon Genes), along with its mutants, pharmaceutically acceptable salts, and hydrate-containing solvates. As a regulator of 173 (TMEM173), especially in the treatment of inflammation, allergies and autoimmune diseases, infectious diseases, various cancers, pre-cancerous syndromes, and as a vaccine adjuvant. International patent application number PCT / IB2017 / 051945 filed internationally on April 5, 2017, the disclosure of which is incorporated herein by reference, and the publication number of the international patent application published internationally on October 12, 2017. It is a compound disclosed and claimed for patent in WO2017 / 175147.

Diseases for which regulation of STING (interferon gene stimulator) is beneficial, such as inflammation, allergies and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, dermatitis, frequent occurrence See its disclosure for systemic administration of Compound A for the treatment of sclerosis, human immunodeficiency virus (HIV) infection, AIDS, cancer, precancerous syndrome, and as an immunogenic composition or vaccine adjuvant. International Patent Application Publication No. PCT / IB2018 / 057738, internationally filed October 4, 2018, and internationally published International Patent Application Publication No. WO2019 / April 11, 2019, incorporated herein by. It is disclosed in 069275.

A pharmaceutical dosage form is a general and useful form of drug for dispensing a pharmaceutically active compound. A variety of such forms are known, including tablets, capsules, pellets, lozenges and powders.

However, it is not always easy to formulate an acceptable pharmaceutical formulation on a commercial scale. The method of formulation and manufacture should be such as to provide a complete dosage form that maintains its integrity until use. Pharmaceutically active compounds with high molecular weight, low solubility and poor oral bioavailability pose specific challenges in the preparation of high quality dosage forms as the physical properties of the drug affect the properties of the dosage form. May bring. The formulator must weigh the unique properties of the drug against the properties of each excipient in order to prepare a safe, effective and easy-to-use pharmaceutical formulation.

WO2017 / 175147 WO 2019/069275

Compound A is a high molecular weight compound (MW849.937), which is suitable for systemic administration and is suitable for the formulator when an attempt is made to formulate this compound into a suitable dosage form having a desired pharmacokinetic profile. Brings your own concerns. Such concerns include, but are not limited to, the tendency of compounds A's salts and solvates to be highly hygroscopic, compound A having poor bioavailability and solubility in water. Very low (solubility is less than 0.01 mg / mL). When these concerns become quite real, there are difficulties in formulating compound A.

It would be desirable to provide compound A in pharmaceutical form with the desired pharmacokinetic profile on a commercial scale.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;並びに
c)アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤
を含む医薬製剤に関する。 The present invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) The pharmaceutical preparation containing a solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid.

In certain embodiments of the invention, the pharmaceutical product is prepared as an aqueous solution containing 2 mg of Compound A, 96 mg of mannitol, and 5.32 mg of L-aspartic acid. The solution is subsequently filled into vials and lyophilized into powder or cake. The lyophilized powder or cake is then reconstituted for use by dilution with a diluent, preferably water.

In certain embodiments of the invention, the pharmaceutical product is prepared as an aqueous solution containing 1 mg of Compound A, 48 mg of mannitol, and 2.66 mg of L-aspartic acid. The solution is subsequently filled into vials and lyophilized into powder or cake. The lyophilized powder or cake is then reconstituted for use by dilution with a diluent, preferably water.

In certain embodiments of the invention, the pharmaceutical product is prepared as an aqueous solution containing about 0.5 mg of Compound A, about 48 mg of mannitol, and 1.3 mg of L-aspartic acid. The solution is subsequently filled into vials and lyophilized into powder or cake. The lyophilized powder or cake is then reconstituted for use by dilution with a diluent, preferably water.

Another aspect of the invention relates to the step of changing the drug concentration from 0.1 mg / mL in water to 4 mg / mL by adjusting the pH with suitable concentrations of asparagine and mannitol for isotonicity. The solution can then be filled into vials and lyophilized into powders or cakes for reconstitution. In addition, the concentration of drug in the reconstitution medium can be varied by the volume of the reconstitution medium added to the lyophilized powder or cake.

Another aspect of the invention is inflammation, allergies and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, dermatitis, polysclerosis, human immunodeficiency virus. A method of treating a disease state selected from (HIV) infection, AIDS, cancer and precancerous syndrome, in which a therapeutically effective amount of a pharmaceutical form of the invention is administered to a patient in need of such treatment. On how to include steps to do.

Another aspect of the invention relates to a method of treating cancer, comprising the step of administering a therapeutically effective amount of a pharmaceutical dosage form of the invention to a patient in need of such treatment.

The present invention is directed to an injectable, preferably lyophilized pharmaceutical composition that is safe, stable and particularly useful for delivering Compound A to a patient in need.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;
c)約2～4の間のpHをもたらすのに有効な量の、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers;
c) A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid in an effective amount to bring about a pH between about 2-4; and optionally.
d) Regarding pharmaceutical products containing water.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;
c)約2.7～3.6の間のpHをもたらすのに有効な量の、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers;
c) A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid in an effective amount to bring about a pH between about 2.7 and 3.6; and optionally.
d) Regarding pharmaceutical products containing water.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;
c)約2.9～3.5の間のpHをもたらすのに有効な量の、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers;
c) A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid in an effective amount to bring about a pH between about 2.9 and 3.5; and optionally.
d) Regarding pharmaceutical products containing water.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;
c)約3.0～3.5の間のpHをもたらすのに有効な量の、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers;
c) A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid in an effective amount to bring about a pH between about 3.0 and 3.5; and optionally.
d) Regarding pharmaceutical products containing water.

を有する薬学的有効量の化合物A;
b)約2～4の間のpHをもたらすのに有効な、薬学的に許容される量の可溶化剤;並びに
c)薬学的に許容され、場合により凍結乾燥ケーキを形成する量の充填剤、例えばマンニトール
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A;
b) A pharmaceutically acceptable amount of solubilizer effective to provide a pH between about 2-4;
c) With respect to pharmaceutical formulations containing, for example, mannitol, an amount of a pharmaceutically acceptable filler that optionally forms a lyophilized cake.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;並びに
c)化合物A:可溶化剤のモル比が約1:1～1:125である、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) Compound A: A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid, with a molar ratio of solubilizer of approximately 1: 1 to 1: 125; and optionally.
d) Regarding pharmaceutical products containing water.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;並びに
c)化合物A:可溶化剤のモル比が約1:1～1:30である、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) Compound A: A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid, with a molar ratio of solubilizer of approximately 1: 1 to 1:30; and optionally.
d) Regarding pharmaceutical products containing water.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;並びに
c)化合物A:可溶化剤のモル比が約1:1～1:100である、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) Compound A: A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid, with a molar ratio of solubilizer of approximately 1: 1 to 1: 100; and optionally.
d) Regarding pharmaceutical products containing water.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;並びに
c)化合物A:可溶化剤のモル比が約1:10～1:30である、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) Compound A: A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid, with a molar ratio of solubilizer of approximately 1: 10 to 1:30; and optionally.
d) Regarding pharmaceutical products containing water.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;並びに
c)1.0mgの化合物Aあたり約0.3mg～約4mgの量の、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) The pharmaceutical formulation comprising a solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid in an amount of about 0.3 mg to about 4 mg per 1.0 mg of Compound A.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)1.0mgの化合物Aあたり約1mg～約4mgの量のアスパラギン酸
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) The pharmaceutical preparation containing aspartic acid in an amount of about 1 mg to about 4 mg per 1.0 mg of Compound A.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)1.0mgの化合物Aあたり約0.5mg～約10mgの量のアスパラギン酸
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) The pharmaceutical preparation containing aspartic acid in an amount of about 0.5 mg to about 10 mg per 1.0 mg of Compound A.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)1.0mgの化合物Aあたり約0.5mg～約6mgの量のアスパラギン酸
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) The pharmaceutical preparation containing aspartic acid in an amount of about 0.5 mg to about 6 mg per 1.0 mg of Compound A.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)1.0mgの化合物Aあたり約1mg～約4mgの量のアスパラギン酸
を含む、医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) For pharmaceutical formulations containing aspartic acid in an amount of about 1 mg to about 4 mg per 1.0 mg of Compound A.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)1.0mgの化合物Aあたり約1.5mg～約3.5mgの量のアスパラギン酸
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) The pharmaceutical preparation containing aspartic acid in an amount of about 1.5 mg to about 3.5 mg per 1.0 mg of Compound A.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)1.0mgの化合物Aあたり約2mg～約3mgの量のアスパラギン酸
を含む、医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) For pharmaceutical formulations containing aspartic acid in an amount of about 2 mg to about 3 mg per 1.0 mg of Compound A.

を有する約0.1mg～約4mgの化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)1.0mgの化合物Aあたり約2mg～約3mgの量のアスパラギン酸
を含む、医薬製剤に関する。 In one embodiment, the invention
a) Structure

About 0.1 mg to about 4 mg of compound A,
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) For pharmaceutical formulations containing aspartic acid in an amount of about 2 mg to about 3 mg per 1.0 mg of Compound A.

を有する約0.1mg～約4mgの化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;並びに
c)化合物A:可溶化剤のモル比が約1:1～1:25である、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

About 0.1 mg to about 4 mg of compound A,
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) Compound A: A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid, with a molar ratio of solubilizer of approximately 1: 1 to 1:25; and optionally.
d) Regarding pharmaceutical products containing water.

を有する約0.5mg～約1.5mgの化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;並びに
c)化合物A:可溶化剤のモル比が約1:1～1:25である、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

About 0.5 mg to about 1.5 mg of compound A,
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) Compound A: A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid, with a molar ratio of solubilizer of approximately 1: 1 to 1:25; and optionally.
d) Regarding pharmaceutical products containing water.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)1.0mgの化合物Aあたり約2.66mgの量のアスパラギン酸
を含む医薬製剤に関する。 In one embodiment, the invention
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) For pharmaceutical formulations containing aspartic acid in an amount of approximately 2.66 mg per 1.0 mg of Compound A.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;
c)アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤; 及び
d)水
を合わせて混合物とするステップ;並びに
2)場合により混合物を蒸発又は凍結乾燥させて、粉末又はケーキを形成するステップ
を含む方法に関する。 In one embodiment, the present invention is a method of producing a pharmaceutical preparation.
1)
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers;
c) A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid; and
d) Steps to combine water into a mixture;
2) It relates to a method comprising a step of optionally evaporating or lyophilizing the mixture to form a powder or cake.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)約2～4の間のpHをもたらすのに有効な量の、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤
を合わせて混合物とするステップ、
2)水を添加して混合物を可溶化するステップ、並びに
3)混合物を蒸発させて、粉末を形成するステップ
を含む方法に関する。 In one embodiment, the present invention is a method of producing a pharmaceutical preparation.
1)
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) A step of combining solubilizers selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid in an amount effective to bring a pH between about 2-4 into a mixture,
2) Add water to solubilize the mixture, as well as
3) The present invention relates to a method comprising evaporating a mixture to form a powder.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)約2～4の間のpHをもたらすのに有効な量の、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤
を合わせて混合物とするステップ、
2)水を添加して混合物を可溶化するステップ、並びに
3)混合物を凍結乾燥させて、粉末又はケーキを形成するステップ
を含む方法に関する。 In one embodiment, the present invention is a method of producing a pharmaceutical preparation.
1)
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) A step of combining solubilizers selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid in an amount effective to bring a pH between about 2-4 into a mixture,
2) Add water to solubilize the mixture, as well as
3) The present invention relates to a method comprising lyophilizing the mixture to form a powder or cake.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)約2～4の間のpHをもたらすのに有効な量の、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤
を合わせて混合物とするステップ、
2)水を添加して混合物を可溶化するステップ、
3)混合物を凍結乾燥させて、粉末又はケーキを形成するステップ、並びに
4)場合により水を添加して、注射用液剤を形成するステップ
を含む方法に関する。 In one embodiment, the present invention is a method of producing a pharmaceutical preparation.
1)
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) A step of combining solubilizers selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid in an amount effective to bring a pH between about 2-4 into a mixture,
2) The step of adding water to solubilize the mixture,
3) The steps of lyophilizing the mixture to form a powder or cake, as well as
4) The present invention relates to a method comprising a step of optionally adding water to form an injectable solution.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)1.0mgの化合物Aあたり約0.3mg～約4mgの量の、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤
を合わせて混合物とするステップ、
2)水を添加して混合物を可溶化するステップ、並びに
3)混合物を蒸発させて、粉末を形成するステップ、並びに
4)場合により水を添加して、注射用液剤を形成するステップ
を含む方法に関する。 In one embodiment, the present invention is a method of producing a pharmaceutical preparation.
1)
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) Mixture of solubilizers selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid in an amount of about 0.3 mg to about 4 mg per 1.0 mg of compound A.
2) Add water to solubilize the mixture, as well as
3) Steps to evaporate the mixture to form a powder, as well as
4) The present invention relates to a method comprising a step of optionally adding water to form an injectable solution.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)化合物A:可溶化剤のモル比が約1:10～1:25である、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される可溶化剤
を合わせて混合物とするステップ、
2)水を添加して混合物を可溶化するステップ、
3)混合物を凍結乾燥させて、粉末又はケーキを形成するステップ、並びに
4)場合により水を添加して、注射用液剤を形成するステップ
を含む方法に関する。 In one embodiment, the present invention is a method of producing a pharmaceutical preparation.
1)
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) Compound A: A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid having a molar ratio of solubilizer of approximately 1: 10 to 1:25 is combined with the mixture. Steps to do,
2) The step of adding water to solubilize the mixture,
3) The steps of lyophilizing the mixture to form a powder or cake, as well as
4) The present invention relates to a method comprising a step of optionally adding water to form an injectable solution.

を有する薬学的有効量の化合物A、
又はその互変異性体、
又はその薬学的に許容される塩;
b)充填剤又は充填剤の組合せ;及び
c)1.0mgの化合物Aあたり約1mg～約4mgの量のアスパラギン酸
を合わせて混合物とするステップ、
2)水を添加して混合物を可溶化するステップ、
3)混合物を凍結乾燥させて、粉末又はケーキを形成するステップ、並びに
4)場合により水を添加して、注射用液剤を形成するステップ
を含む方法に関する。 In one embodiment, the present invention is a method of producing a pharmaceutical preparation.
1)
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers; and
c) Steps to combine aspartic acid in an amount of about 1 mg to about 4 mg per 1.0 mg of compound A into a mixture,
2) The step of adding water to solubilize the mixture,
3) The steps of lyophilizing the mixture to form a powder or cake, as well as
4) The present invention relates to a method comprising a step of optionally adding water to form an injectable solution.

を有する薬学的有効量の化合物A
b)薬学的に許容される量の充填剤又は充填剤の組合せ;
c)薬学的に許容されるpHをもたらすのに有効な、アスパラギン酸、酢酸、グルタミン酸及びグルクロン酸から選択される、薬学的に許容される量の可溶化剤;並びに場合により
d)水
を含む医薬製剤に関する。 In one embodiment, the invention
It is a pharmaceutical product for intravenous administration to patients who need it.
a) Structure

Pharmaceutically effective amount of compound A with
b) A pharmaceutically acceptable amount of filler or combination of fillers;
c) A pharmaceutically acceptable amount of solubilizer, selected from aspartic acid, acetic acid, glutamic acid and glucuronic acid, which is effective in producing a pharmaceutically acceptable pH; and optionally.
d) Regarding pharmaceutical products containing water.

を有する化合物Aを含む医薬製剤を作製する方法であって、
a)アスパラギン酸、酢酸、グルタミン酸及びグルクロン酸から選択される可溶化剤を水に添加して、溶液を形成するステップ;
b)化合物Aを添加して、pHを約3.0～3.3の間に維持しながら溶解するステップ;
c)充填剤又は充填剤の組合せを溶液中に溶解するステップ;
d)そのように調製した溶液を濾過するステップ;
e)場合により濾過した溶液を凍結乾燥バイアル中に充填し、約-45℃で凍結させるステップ;並びに
f)場合により凍結した溶液をフリーズドライするステップ
を含む方法に関する。 In one embodiment, the invention is structural.

It is a method for producing a pharmaceutical preparation containing compound A having the above.
a) The step of adding a solubilizer selected from aspartic acid, acetic acid, glutamic acid and glucuronic acid to water to form a solution;
b) The step of adding compound A and dissolving while maintaining the pH between about 3.0 and 3.3;
c) The step of dissolving the filler or the combination of fillers in the solution;
d) The step of filtering the solution so prepared;
e) Optionally fill a lyophilized vial with the filtered solution and freeze at about -45 ° C; as well.
f) It relates to a method including a step of freeze-drying a frozen solution in some cases.

In one embodiment, the present invention is a method of treating a disease in which regulation of STING (interferon gene stimulating factor) is beneficial in a patient in need of treatment, wherein the patient is in an amount of about 0.5 mg / ml to about. Steps to intravenously administer an effective amount of a formulation containing 6 mg / ml Compound A, about 20 mg / ml to about 200 mg / ml mannitol, about 2.66 mg of aspartic acid per 1.0 mg of Compound A, and water. Regarding methods, including.

In one embodiment, the invention provides a pharmaceutical formulation of the invention for use in the treatment of diseases for which regulation of STING is beneficial.

を有する化合物A
又はその互変異性体、
又はその薬学的に許容される塩を含む医薬製剤を作製する方法であって、
a)
i)アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される少なくとも1つの可溶化剤;
ii)pHが約3.0～3.5の間に維持されている化合物A又はその互変異性体若しくは薬学的に許容される塩;
iii)充填剤又は充填剤の組合せ;及び
Iv)水
を含む溶液を形成するステップ;
b)場合により溶液を濾過するステップ;
c)場合により濾過した溶液を凍結乾燥バイアル中に充填し、約-45℃で凍結するステップ;並びに
d)凍結した溶液をフリーズドライする、又は凍結されていない溶液を蒸発させるステップ
を含む、方法に関する。 In one embodiment, the invention is structural.

Compound A with
Or its tautomer,
Or a method for producing a pharmaceutical preparation containing a pharmaceutically acceptable salt thereof.
a)
i) At least one solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid;
ii) Compound A or its tautomer or pharmaceutically acceptable salt whose pH is maintained between about 3.0 and 3.5;
iii) Filler or combination of fillers; and
Iv) Steps to form a solution containing water;
b) In some cases filtering the solution;
c) Optionally fill a lyophilized vial with filtered solution and freeze at about -45 ° C; as well.
d) The method comprises the steps of freeze-drying the frozen solution or evaporating the unfrozen solution.

を有する化合物A
又はその互変異性体、
又はその薬学的に許容される塩を含む医薬製剤を作製する方法であって;
a)
i)アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される少なくとも1つの可溶化剤;
ii)pHが約3.0～3.5の間に維持されている化合物A又はその互変異性体若しくは薬学的に許容される塩;
iii)充填剤又は充填剤の組合せ;及び
Iv)水
を含む溶液を形成するステップ;
b)場合により溶液を濾過するステップ;
c)場合により濾過した溶液を凍結乾燥バイアル中に充填し、約-45℃で凍結するステップ;
d)凍結した溶液をフリーズドライする、又は凍結されていない溶液を蒸発させるステップ;並びに
(e)場合により水を添加して、注射用液剤を形成するステップ
を含む方法に関する。 In one embodiment, the invention is structural.

Compound A with
Or its tautomer,
Or a method of making a pharmaceutical product containing a pharmaceutically acceptable salt thereof;
a)
i) At least one solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid;
ii) Compound A or its tautomer or pharmaceutically acceptable salt whose pH is maintained between about 3.0 and 3.5;
iii) Filler or combination of fillers; and
Iv) Steps to form a solution containing water;
b) In some cases filtering the solution;
c) Optionally fill a lyophilized vial with filtered solution and freeze at about -45 ° C;
d) Freeze-dry the frozen solution or evaporate the unfrozen solution;
(e) The present invention relates to a method comprising a step of optionally adding water to form an injectable solution.

を有する化合物A
又はその互変異性体、
又はその薬学的に許容される塩を含む医薬製剤を作製する方法であって;
a)
i)化合物A:可溶化剤のモル比が約1:1～1:125である、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される少なくとも1つの可溶化剤;
ii)pHが約3.0～3.5の間に維持されている、約0.1～約4mgの化合物A又はその互変異性体若しくは薬学的に許容される塩;
iii)1.0mgの化合物Aあたり約20mg～約200mgの量の、充填剤又は充填剤の組合せ;及び
Iv)水
を含む溶液を形成するステップ;
b)場合により溶液を濾過するステップ;
c)場合により濾過した溶液を凍結乾燥バイアル中に充填し、約-45℃で凍結するステップ;
d)凍結した溶液をフリーズドライする、又は凍結されていない溶液を蒸発させるステップ;並びに
(e)場合により水を添加して、注射用液剤を形成するステップ
を含む方法に関する。 In one embodiment, the invention is structural.

Compound A with
Or its tautomer,
Or a method of making a pharmaceutical product containing a pharmaceutically acceptable salt thereof;
a)
i) Compound A: At least one solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid, having a molar ratio of solubilizer of about 1: 1 to 1: 125;
ii) About 0.1 to about 4 mg of Compound A or its tautomer or pharmaceutically acceptable salt whose pH is maintained between about 3.0 and 3.5;
iii) Fillers or combinations of fillers in an amount of about 20 mg to about 200 mg per 1.0 mg of Compound A; and
Iv) Steps to form a solution containing water;
b) In some cases filtering the solution;
c) Optionally fill a lyophilized vial with filtered solution and freeze at about -45 ° C;
d) Freeze-dry the frozen solution or evaporate the unfrozen solution;
(e) The present invention relates to a method comprising a step of optionally adding water to form an injectable solution.

を有する化合物A
又はその互変異性体、
又はその薬学的に許容される塩を含む医薬製剤を作製する方法であって;
a)
i)化合物A:可溶化剤のモル比が約1:1～1:100である、アスパラギン酸、酢酸、グルタミン酸、メタンスルホン酸、乳酸及びグルクロン酸から選択される少なくとも1つの可溶化剤;
ii)pHが約3.0～3.5の間に維持されている、約0.5～約1.5mgの化合物A又はその互変異性体若しくは薬学的に許容される塩;
iii)1.0mgの化合物Aあたり約20mg～約200mgの量の充填剤又は充填剤の組合せ;及び
Iv)水
を含む溶液を形成するステップ;
b)場合により溶液を濾過するステップ;
c)場合により濾過した溶液を凍結乾燥バイアル中に充填し、約-45℃で凍結するステップ;
d)凍結した溶液をフリーズドライする、又は凍結されていない溶液を蒸発させるステップ;並びに
(e)場合により水を添加して、注射用液剤を形成するステップ
を含む方法に関する。 In one embodiment, the invention is structural.

Compound A with
Or its tautomer,
Or a method of making a pharmaceutical product containing a pharmaceutically acceptable salt thereof;
a)
i) Compound A: At least one solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid, with a molar ratio of solubilizer of about 1: 1 to 1: 100;
ii) About 0.5 to about 1.5 mg of Compound A or its tautomer or pharmaceutically acceptable salt whose pH is maintained between about 3.0 and 3.5;
iii) Fillers or combinations of fillers in an amount of about 20 mg to about 200 mg per 1.0 mg of Compound A; and
Iv) Steps to form a solution containing water;
b) In some cases filtering the solution;
c) Optionally fill a lyophilized vial with filtered solution and freeze at about -45 ° C;
d) Freeze-dry the frozen solution or evaporate the unfrozen solution;
(e) The present invention relates to a method comprising a step of optionally adding water to form an injectable solution.

を有する化合物A
又はその互変異性体、
又はその薬学的に許容される塩を含む医薬製剤を作製する方法であって;
a)
i)1.0mgの化合物Aあたり約2mg～約3mgの量のアスパラギン酸;
ii)pHが約3.0～3.5の間に維持されている、約0.5～約1.5mgの化合物A又はその互変異性体若しくは薬学的に許容される塩;
iii)1.0mgの化合物Aあたり80mg～約100mgの量の充填剤又は充填剤の組合せ;及び
Iv)水
を含む溶液を形成するステップ;
b)場合により溶液を濾過するステップ;
c)場合により濾過した溶液を凍結乾燥バイアル中に充填し、約-45℃で凍結するステップ;
d)凍結した溶液をフリーズドライする、又は凍結されていない溶液を蒸発させるステップ;並びに
(e)場合により水を添加して、注射用液剤を形成するステップ
を含む方法に関する。 In one embodiment, the invention is structural.

Compound A with
Or its tautomer,
Or a method of making a pharmaceutical product containing a pharmaceutically acceptable salt thereof;
a)
i) Aspartic acid in an amount of about 2 mg to about 3 mg per 1.0 mg of Compound A;
ii) About 0.5 to about 1.5 mg of Compound A or its tautomer or pharmaceutically acceptable salt whose pH is maintained between about 3.0 and 3.5;
iii) Fillers or combinations of fillers in an amount of 80 mg to about 100 mg per 1.0 mg of Compound A; and
Iv) Steps to form a solution containing water;
b) In some cases filtering the solution;
c) Optionally fill a lyophilized vial with filtered solution and freeze at about -45 ° C;
d) Freeze-dry the frozen solution or evaporate the unfrozen solution;
(e) The present invention relates to a method comprising a step of optionally adding water to form an injectable solution.

Due to the poor oral bioavailability of Compound A, oral administration, for example by tablets, capsules, pellets, lozenges or powders, was not available. As a result, a suitable formulation for parenteral administration was sought. In order for compound A to be administered by parenteral administration, the compound must be available in a suitable vehicle-dissolved form. To meet this need, a pharmaceutical concentration of ≧ 0.1 mg / mL, preferably ≧ 0.5 mg / mL, preferably ≧ 1.0 mg / mL is desirable, but this is difficult due to the low solubility of compound A. Is. Preferably, the concentration is in the range of 0.1 mg / mL to 4 mg / mL. The pharmaceutical composition of the present invention can be injected "as is" via an intravenous bolus or can be further diluted with a suitable medium for intravenous injection, such as dextrose (D5W), thereby being defective. Designed to be soluble / bioavailable and satisfy pH and weight osmolality to solve the challenges of bioavailability and formulation of compound A, a compound with low solubility, into acceptable pharmaceutical forms. Will be done.

One option in the formulation of compound A for parenteral administration is to form in the formulation a crystallized salt, hydrate or solvate of the compound that exhibits sufficient solubility. Attempts to prepare compound A in stable crystalline form as a salt, hydrate, or solvate have been shown to be difficult. These alternative forms of compound A are generally very hygroscopic, which tends to result in dosage variability and increased degradation products, making them unsuitable for pharmaceutical formulations.

An IV (intravenous) formulation was attempted. Formulations in the pH range of 4-9 are generally considered for IV administration. Formulations near extremes in this pH range, especially low extremes, are of particular concern due to complications including severe irritation of the injection site and thrombophlebitis. In order to minimize irritation during administration, pharmaceutical excipients of the pharmaceutical product, especially counterion and buffering capacity, are important. Non-physiological pH formulations tend to precipitate in the blood after injection due to the reduced solubility at normal human pH of 7.4 and may cause thrombophlebitis (SH YALKOWSKY Journal of). Pharmaceutical Sciences Vol. 87, No. 7, pp. 787-796, July 1998). It is an object of the present invention to provide an IV formulation of Compound A either directly or following dilution in a suitable vehicle to avoid irritation of the injection site during administration. It is also an object of the present invention to prevent thrombophlebitis upon injection of the formulation of compound A either directly or following dilution in a suitable medium. As shown in Example 17, the pharmaceutical product of the present invention has been found to be safe for IV bolus administration.

Surprisingly, the pH max (pH of maximum solubility) for compound A is counterion dependent, where the concentration of the ionized form provides sufficient solubility to maintain a physically stable solution. found.

The pharmaceutical product of the present invention provides enhanced chemical stability and solubility in the pharmaceutical composition. The injectable dose of Compound A and the use of selected solubilizers to prepare the dry powder, preferably lyophilized dry powder, are suitable for parenteral administration of stable and soluble formulations. Brings generation. A more stable formulation results in an extended pharmaceutical shelf life with significant economic benefits.

Compound A, in particular the free base, is reconstituted from a lyophilized formulation when in an aqueous formulation with the solubilizer of choice or prepared with the solubilizer of choice, preferably the solubilizer. When is an organic acid, it has been found to be significantly more water soluble and more stable. In a preferred embodiment, the solubilizer is selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid or glucuronic acid. It is understood that combinations of these acids are also useful in the present invention. Preferably, the solubilizer is acetic acid. Preferably, the solubilizer is glutamic acid. Preferably, the solubilizer is methanesulfonic acid. Preferably, the solubilizer is lactic acid. Preferably, the solubilizer is glucuronic acid. Most preferably, the solubilizer is aspartic acid. Preferably, the solubilizer is selected from aspartic acid, acetic acid, glutamic acid and glucuronic acid.

As used herein, the term aspartic acid includes all forms of aspartic acid, including D-aspartic acid, L-aspartic acid and combinations thereof, which are equivalent for use in the present invention. Conceivable.

As used herein, all pH indications and ranges are considered to be measured at room temperature (RT), unless otherwise defined. Preferably, RT is about 23 ° C.

As used herein, compound A is in any form, i.e. any metamorphic form, any isomer form, any salt or non-salt form (eg, free acid or base form, or salt). , Especially its pharmaceutically acceptable salt), as well as any of its physical forms (eg, non-solid form (eg, liquid or semi-solid form), and solid form (eg, amorphous or crystalline form), specific polymorphs. Includes compounds in morphology, hydrated forms (including solvate forms including, for example, mono, di, and hemi hydrates), as well as mixtures of various forms.

It is understood that compound A or a pharmaceutically acceptable salt thereof or a solvate thereof (particularly a hydrate) can be present in crystalline, non-crystalline or a mixture thereof. Compounds or salts or solvates thereof (particularly hydrates) may also exhibit polymorphisms (ie, the ability to occur in different crystalline forms). These different crystalline morphologies are typically known as "polymorphs". It will be appreciated that the invention includes all polymorphs of compound A, including any salt and / or solvate thereof (particularly a hydrate) and mixtures thereof.

By utilizing the solubilizer of choice, the product becomes more stable, contains less unwanted degradation products, is highly soluble and extends the shelf life of the composition.

The present invention is directed to a preparation containing an excipient suitable for administration of Compounds A and IV. Unless otherwise noted, it is understood that the formulation can be an aqueous formulation ready for injection or a dry solid formulation that requires reconstitution prior to administration, such as a powder formulation, preferably a lyophilized formulation. .. When specifying the amount of compound A or excipient used in the formulation of the present invention, the amount may be by weight, eg mg, or by concentration, eg mg / mL, or the effect that the excipient has on the formulation. , For example, by the amount required to produce a particular pH or range. Regardless of the method in which the amount is indicated, it is understood that the amount is based on a concentration of mg / mL. For example, if the amount of aspartic acid is shown as 2 mg / mL, this is equal to 2 mg aspartic acid as a solid in a vial intended to be reconstituted into 1 mL, or 2 mg aspartic acid per 1 mL of water. Would be equivalent to an aqueous formulation containing. If necessary, the formulation can be subsequently diluted for infusion. The formulations of the present invention are 2-4, preferably about 2.5-about 3.8, preferably about 2.7-about 3.6, preferably about 2.9-about 3.5, preferably about 3.0-about 3.5, preferably about. 3. Selected solubilization of an amount effective to bring about a pH environment in the range of preferably about 3.1, preferably about 3.2, preferably about 3.3, preferably about 3.4, preferably about 3.5. The agent, preferably aspartic acid, preferably acetic acid, preferably glutamic acid, preferably glucuronic acid, preferably methanesulfonic acid, preferably lactic acid. Aspartic acid is particularly advantageous as it has surprisingly been found to solubilize compound A at higher concentrations than other inorganic and organic acids. Depending on the amount relative to compound A, asparagic acid may be added to compound A up to about 6 mg / mL; preferably up to about 4 mg / mL, preferably about 0.1 mg / mL to about 6 mg / mL; preferably. Approximately 0.5 mg / mL to approximately 4 mg / mL; preferably approximately 1 mg / mL to approximately 4 mg / mL; preferably approximately 2 mg / mL to approximately 4 mg / mL; preferably approximately 2 mg / mL; preferably approximately 3 mg Solubilize at / mL.

Preferably, compound A is about 0.1 mg to about 6 mg in dosage form; preferably about 0.1 mg to about 4 mg; preferably about 1 mg to about 5 mg; preferably about 0.5 mg to about 2 mg; preferably about 0.5 mg to about 2 mg. Approximately 2 mg to approximately 4 mg; preferably approximately 0.1 mg; preferably approximately 0.2 mg; preferably approximately 0.3 mg; preferably approximately 0.4 mg; preferably approximately 0.5 mg; preferably approximately 0.6 mg; preferred Is about 0.7 mg; preferably about 0.8 mg; preferably about 0.9 mg; preferably about 1 mg; preferably about 1.25 mg; preferably about 1.5 mg; preferably about 2 mg; preferably about 3 mg It is preferably present in an amount of about 4 mg.

Those skilled in the art will appreciate the method of lyophilization, and that this method results in the formation of powder or cake. As used in the art and herein, both powders and cakes are considered equivalent.

Preferably, compound A is about 0.5 mg to about 6 mg; preferably about 1 mg to about 5 mg; preferably about 2 mg to about 4 mg; preferably about 0.5 mg; preferably about 1 mg; preferably about 1 mg. Is present in an amount of about 2 mg; preferably about 3 mg; preferably about 4 mg.

The amount of solubilizer required, preferably L-aspartic acid, depends on the amount of compound A in the formulation, typically from about 0.5 mg / mL to about 4 mg / mL, preferably about 1 mg / mL. It is present in the range of mL to about 3.5 mg / mL, preferably about 1.5 mg / mL to about 3 mg / mL, preferably about 2 mg / mL to about 3 mg / mL, and preferably about 2.66 mg / mL.

The amount of solubilizer required, preferably L-aspartic acid, depends on the amount of compound A in the formulation, typically from about 0.5 mg / mL to about 3 mg / mL, preferably about 1 mg / mL. It is present in the range of mL to about 3 mg / mL.

Preferably, the amount of solubilizer, preferably L-aspartic acid, in the formulation is about 2.66 mg per 1.0 mg of compound A, preferably about 0.1 mg to about 10 mg per 1.0 mg of compound A, preferably. Is about 0.5 mg to about 10 mg per 1.0 mg of compound A, preferably about 0.5 mg to about 6 mg per 1.0 mg of compound A, preferably about 1 mg to about 4 mg per 1.0 mg of compound A, preferably 1.0 mg. About 1.5 mg to about 3.5 mg per compound A, preferably about 2 mg to about 3 mg per 1.0 mg of compound A.

As used herein, when the amount of solubilizer, eg aspartic acid, is expressed in terms such as effective to bring about a particular pH, the intended amount of solubilizer is, for example, 1 mL. It is understood that the amount will result in a particular pH upon reconstruction at room temperature with water. In one embodiment, the phrase "effective amount to bring about a particular pH" means water 0.5 mL, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 15 mL, 20 mL, In an amount of 30 mL, 40 mL, 50 mL or 100 mL, it means an amount that gives a specific pH when added to the dry powder or lyophilized cake of the present invention at room temperature.

Preferably, the pharmaceutical product of the present invention is provided as a dry powder in a closed vial. In one embodiment, the dry powder is a lyophilized powder or cake containing compound A; or with a suitable medium for "as is" injection or intravenous injection via an intravenous bolus, such as dextrose (D5W). It is an IV preparation containing compound A suitable for further dilution of.

As used herein, the filler is an excipient, eg, an excipient saccharide, used to provide a suitable dry powder for formulation with compound A. In one embodiment, the dry powder is a lyophilized powder or cake. Suitable fillers for use in the present invention include mannitol, mannose, melibiose, octulose, fructose, lactose, sucrose, trehalose, sorbitol, glucose, galactose, glycine, dextrose, raffinose, ribose, xylitol, xylose, cyclodextrin. , Dextran, cellulose, povidone, PEG (eg, PEG300, PEG400, PEG3350, PEG6000, PEG8000, etc.), polygalacturonic acid, galacturonic acid, amino acids (including amino acid salts) such as lysine, arginine, glycine and galactose, alone or Listed in combination. In one embodiment, the dry powder provides dilution of the active ingredient through the powder and the final formulation. Suitable fillers useful in the present invention consist essentially of sucrose, lactose, mannitol, dextrose or a combination thereof. Preferably, the filler is mannitol, preferably D-mannitol. Suitable fillers useful in the present invention include sucrose, lactose, mannitol, dextrose or combinations thereof. Suitable fillers useful in the present invention include sucrose, lactose, mannitol or combinations thereof. The filler is generally in an amount of about 20 to about 200 mg / mL; preferably about 40 to about 150 mg / mL; preferably about 80 mg / mL to about 100 mg / mL, preferably about 48 mg / mL. exist. The filler is generally present in an amount of about 20 to about 200 mg, preferably about 40 to about 150 mg; preferably about 80 mg to about 100 mg, preferably about 48 mg per 1.0 mg of Compound A. Preferably, the filler is mannitol and the amount of mannitol in the formulation is about 48 mg per 1.0 mg of compound A. In one embodiment, the amount of filler shown is sufficient to form a lyophilized powder or cake.

The composition can also include other pharmaceutically acceptable diluents, excipients or carriers. The formulation is suitable for long-term storage in glass containers commonly used in the pharmaceutical industry, such as standard USP type I borosilicate glass containers.

An aqueous injectable composition of compound A (or drug as used herein) comprises a solubilizer, eg, an excipient containing aspartic acid, preferably L-aspartic acid, and the drug in water. It can be manufactured by adjusting at a suitable temperature. One aspect of the invention relates to the step of adjusting the drug: solubilizer ratio, preferably the drug: aspartic acid ratio, to achieve the required drug solubility and pH in the formulation. The molar ratio of this compound A: solubilizer is generally about 1: 1 to 1: 125, preferably 1: 1 to 1: 100, preferably 1: 1 to 1:30, preferably. The ratio can be in the range of about 1:10 to 1:30, preferably about 1:10 to 1:25, preferably about 1:15 to 1:25, preferably around 1:20. An aqueous injectable composition of compound A can be prepared by first dissolving a solubilizer, preferably aspartic acid, in water and then dissolving compound A in an acid medium at a suitable temperature. can. The filler, preferably mannitol, is added to the above solution to adjust the weight osmolality and the batch is aliquoted to the required volume with water for injection. The solution is aseptically filtered through a sterile filter and aseptically filled into a sealed, prewashed, presterilized / depyrogenized USP Type I clear glass vial. To produce the lyophilized dosage form, the filled vials can then be lyophilized and then plugged and sealed under a nitrogen flush using, for example, a prewashed and pre-sterilized 20 mm gray stopper. can.

In one embodiment of the invention, the compositions of the invention are generally made as follows:
1. A solution of selected solubilizer, preferably aspartic acid, preferably acetic acid, preferably glutamic acid, preferably glucuronic acid, preferably methanesulfonic acid, preferably lactic acid, added to water. Form;
2. Add compound A and maintain pH between about 2.0-4.0, eg 3.0-3.5 to dissolve;
3. Add filler, preferably mannitol, to the solution;
4. Filter the solution, fill in lyophilized vials and freeze at about -45 ° C;
5. Freeze-dry the frozen product at about -20 ° C and secondarily dry it between about 25-45 ° C; and
6. Plug the lyophilized vial and store at approximately 25 ° C.

The lyophilized preparation produced is reconstituted with a suitable diluent, eg water, at the time of administration, eg, about 1.0 mg / mL, eg, about 2.0 mg / mL, eg, about 4 mg / mL, eg, about 0.5 mg. / mL, eg about 0.1 mg / mL, eg about 0.2 mg / mL, eg about 0.3 mg / mL, eg about 0.4 mg / mL, eg about 0.6 mg / mL, eg about 0.7 mg / mL, eg about 0.8 mg / mL Obtaining a final concentration of compound A or a mutant or hydrate thereof or a pharmaceutically acceptable salt thereof in mL, such as about 0.9 mg / mL, for example about 1.25 mg / mL, for example about 1.5 mg / mL. It can, which is suitable for intravenous administration to patients in need of compound A.

In one embodiment of the invention, the compositions of the invention are generally made as follows:
1. A solution of selected solubilizer, preferably aspartic acid, preferably acetic acid, preferably glutamic acid, preferably glucuronic acid, preferably methanesulfonic acid, preferably lactic acid, added to water. Form;
2. Add compound A and maintain pH between about 2.0-4.0, eg 3.0-3.5 to dissolve;
3. Add filler, preferably mannitol, to the solution;
4. Filter the solution and transfer to a suitable container;
5. Evaporate the formulation to obtain a dry powder; and
6. Place the dry powder in a vial and plug it.

The dry powder formulation produced is reconstituted with a suitable diluent, eg water, upon administration, eg, about 1.0 mg / mL, eg, about 2.0 mg / mL, eg, about 4 mg / mL, eg, about 0.5 mg. / mL, eg about 0.1 mg / mL, eg about 0.2 mg / mL, eg about 0.3 mg / mL, eg about 0.4 mg / mL, eg about 0.6 mg / mL, eg about 0.7 mg / mL, eg about 0.8 mg / mL It is possible to obtain a final concentration of compound A or its tautomers or hydrates or pharmaceutically acceptable salts in mL, such as about 0.9 mg / mL, for example about 1.25 mg / mL, for example about 1.5 mg / mL. It can, which is suitable for intravenous administration to patients in need of compound A.

In one embodiment of the invention, the compositions of the invention are generally made as follows:
1. A solution of selected solubilizer, preferably aspartic acid, preferably acetic acid, preferably glutamic acid, preferably glucuronic acid, preferably methanesulfonic acid, preferably lactic acid, added to water. Form;
2. Add compound A and maintain pH between about 2.0-4.0, eg 3.0-3.5 to dissolve;
3. Add filler, preferably mannitol, to the solution; and
4. Filter the solution and transfer to a container suitable for IV administration.

Parenteral administration constitutes an aspect of any injectable dosage form, and there are several types of IV infusions available for this purpose. The IV solution is often prepared by mixing the IV preparation with a compatible IV infusion. The properties of the IV solution are such that sterility is not compromised, and the drug remains physically and chemically stable in the solution, after mixing the pharmaceutical / reconstituted solution with the IV infusion, the patient. It should cover a suitable period of use before administration to. Alternatively, the solution dosage form can be diluted in a suitable IV mixed medium, such as 5% dextrose, 5% mannitol, for dilution to a dose suitable for administration. The lyophilized form of compound A can be reconstituted with sterile water for injection to obtain a clear solution prior to IV administration using a method similar to that described for solution dosage forms.

The term "pharmaceutically effective amount" of an active ingredient means an amount that elicits a biological or medical response in a tissue, system or animal, preferably human, as sought by a researcher or clinician.

Preferably, as used herein, "patient" refers to a human patient.

The compositions of the invention are in WO2017 / 175147 including cancer, precancerous syndrome, infectious diseases, influenza, HIV, HCV, HPV and HBV infections; as well as inflammation, allergies and autoimmune diseases, skin warts, multiple. It can be administered to patients for the treatment of diseases and disorders as disclosed in WO 2019/069275, including sclerosis and AIDS.

Preferably, the compositions of the invention include brain (neuroglio), glioblastoma, stellate cell tumor, polymorphic glioblastoma, Bannayan-Zonana syndrome, Cowden's disease, Lermittodacross's disease, Wilms. Tumor, Ewing sarcoma, rhizome myoma, lining tumor, myeloma, head and neck, kidney, liver, melanoma, ovary, pancreas, adenocarcinoma, tubular adenocarcinoma, squamous epithelial cancer, pancreatic adenocarcinoma, glucagon Producing tumor, pancreatic islet cell tumor, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, T-cell lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia , Acute myeloid leukemia, Chronic neutrophil leukemia, Acute T-cell lymphoblastic leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma, Giant blast leukemia, multiple myeloma, acute meganuclear blast leukemia, premyelocytic leukemia, red leukemia, malignant lymphoma, hodgkin lymphoma, non-hodgkin lymphoma, T-cell lymphoblastic lymphoma, barkit lymphoma, follicle Sexual lymphoma, neuroblastoma, bladder cancer, urinary tract epithelial cancer, pudendal cancer, cervical cancer, endometrial cancer, renal cancer, mesotheloma, esophageal cancer, salivary adenocarcinoma, liver It is selected from cell cancer, gastric cancer, nasopharangeal cancer, oral cancer, oral cancer (cancer of the mouth), GIST (gastrointestinal stromal tumor) and testicular cancer. Administered to patients for treatment of cancer.

Preferably, the compositions of the invention are non-small cell lung cancer (NSCLC), bladder, squamous cell carcinoma of the head and neck, cervical, endometrial, ovary, pancreas, microsatellite stable colon cancer, high frequency. Microsatellite Instability Administered to patients for the treatment of cancers selected from colorectal cancer, stomach, esophageal endo, esophageal gastric junction, esophagus, squamous cell carcinoma, acute leukemia and triple negative breast cancer ..

Preferably, the compositions of the invention include cervical carcinoma in situ, monoclonal gammopathy of unknown significance (MGUS), myelodysplasia syndrome, poor regenerative anemia, cervical lesions, cutaneous mother spots. In patients for the treatment of precancerous syndromes selected from (premelanoma), carcinoma in situ (intraductal) tumor (PIN), non-invasive ductal carcinoma (DCIS), colon polyps and severe hepatitis or liver cirrhosis. Be administered.

Dosing regimens utilizing the compounds of the invention are selected according to a variety of factors, including the patient's age, weight, gender and medical condition; the severity of the condition being treated; the route of administration; and the patient's renal and liver function. Will be done. The usual skilled physician can easily determine and prescribe the effective amount of drug required to prevent, counteract, or stop the condition.

Intravenously, the preferred dose of Compound A is from about 0.1 mg / mL to about 6 mg / mL; preferably 0.5 mg / mL to about 6 mg / mL; preferably 0.5 mg / mL to about 4 mg / mL; preferably. 0.5 mg / mL to about 2 mg / mL; preferably 0.5 mg / mL to about 1.5 mg / mL; preferably 0.5 mg / mL to about 1 mg / mL; preferably about 1 mg / mL to about 5 mg / mL It is preferably in the range of about 2 mg / mL to about 4 mg / ml; preferably in the range of 2 mg / mL; preferably in the range of 4 mg / mL. For example, the pharmaceutical product of the present invention should have about 0.5 mg / mL to about 6 mg / mL of Compound A for administration to a 50 kg patient.

Intravenously, the most preferred dose of Compound A is from about 0.1 mg / mL to about 4 mg / mL; preferably from about 0.1 mg / mL to about 3 mg / mL; preferably from about 2 mg / mL to about 4 mg / mL; Preferably 2 mg / mL; preferably 1 mg / mL; preferably 0.1 mg / mL; preferably 0.2 mg / mL; preferably 0.3 mg / mL; preferably 0.4 mg / mL; preferably 0.5 mg / mL; preferably 0.6 mg / mL; preferably 0.7 mg / mL; preferably 0.8 mg / mL, preferably 0.9 mg / mL; preferably 1.25 mg / mL; preferably 1.5 mg / mL It is in the range of mL. For example, the pharmaceutical product of the present invention should have about 0.1 mg / mL to about 4 mg / mL of Compound A for administration to a 50 kg patient.

Compound A, which is the active ingredient, can be prepared as described in Example 14 of WO2017 / 175147.

又は(Z)-1-((E)-4-((Z)-5-カルバモイル-2-((1-エチル-3-メチル-1H-ピラゾール-5-カルボニル)イミノ)-7-(3-モルホリノプロポキシ)-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-1-イル)ブタ-2-エン-1-イル)-2-((1-エチル-3-メチル-1H-ピラゾール-5-カルボニル)イミノ)-7-メトキシ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルボキサミド

として存在することができる。 As disclosed in WO2017 / 175147, compound A may be tautomeric or isomeric, eg,
(E) -1-((E) -4-((E) -5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) imino) -7- (3-) Morphorinopropoxy) -2,3-dihydro-1H-benzo [d] imidazole-1-yl) buta-2-en-1-yl) -2-((1-ethyl-3-methyl-1H-pyrazol-5) -Carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide

Or (Z) -1-((E) -4-((Z) -5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) imino) -7- (3) -Morholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazole-1-yl) buta-2-en-1-yl) -2-((1-ethyl-3-methyl-1H-pyrazol-) 5-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide

Can exist as.

All such tautomer and isomer forms, including the mixture, as well as pharmaceutically acceptable salts, solvates and hydrates thereof are included in Compound A.

As used herein, the term "formulation" and its derivatives, unless otherwise defined, are dry powders containing compound A, preferably lyophilized powders or cakes, dry powders, preferably lyophilized. Refers to a solution containing compound A reconstituted from a powder or cake, an injectable solution containing compound A, or a dry mixture of excipients and compound A.

In another embodiment of the present invention, there is provided a formulation of an aqueous injectable dosage form of Compound A and a method for producing the same. The formulations are listed in Table A below. The sterile solution dosage form composition of Compound A shown in Table A is ready for injection because the pH and osmolal concentration of the preparation are adjusted to avoid pain at the injection site.

Another embodiment of the invention provides a lyophilized composition for injection of Compound A and a method for producing the composition. The compositions are listed in Table B below.

In another embodiment of the invention, the composition of Table B is formulated to obtain a lyophilized dosage form with suitable pharmaceutical properties, such as stability and shelf life, and in vials for lyophilization. Filled. In another embodiment of the invention, aspartic acid is another acid such as acetic acid, glucuronic acid, lactic acid, methanesulfonic acid or at least one pKa to optimize the properties of the formulation, eg stability and shelf life. Used with amino acids with ≤4, such as glutamate.

In another embodiment of the invention, there is provided a method of delivering Compound A by a parenteral route including an intravenous, subcutaneous or intraperitoneal route, or a formulation thereof.

In another embodiment of the invention, there is provided a method of delivering compound A by parenteral administration in a dosage form formulated as a solution or a lyophilized or powdered product for reconstitution, or a formulation thereof.

In another embodiment of the invention, a method of solubilizing compound A utilizing the principle of pH-solubility enhancement of a drug's free base with a suitable "solubilizer", or compound A. A solubilized composition comprising is provided. Suitable solubilizers are capable of enhancing the solubility of compound A in the desired formulation.

In another embodiment of the invention, a method for achieving solubility of compound A in the pH range of 2-4, preferably 3.0-3.5 for parenteral formulations, or a solubilized composition comprising compound A. The thing is provided. The desired solubility is based on the dose requirements for a particular route of administration in order to achieve a physiological response during parenteral administration.

In another embodiment of the invention, a suitable solubilizer for a parenteral formulation due to the preferred pH max is provided such that the pH of the formulation is in the pH range of 2-4, preferably 3.0-3.5. A method of achieving the solubility of compound A prepared using it, or a solubilized composition comprising compound A is provided.

In another embodiment of the invention, compound A has a pH in the range of 2-4, preferably 3.0-3.5, preferably 3.0-3.2, preferably 3.2, preferably 3.5 within the pHmax region. A method of formulating using an excess solubilizer or a formulated composition containing compound A is provided while maintaining the above.

In another embodiment of the invention, compound A, in addition to its main role as a counterion, uses an appropriate excess solubilizer as a buffer to prevent disproportionation of the free base. A method for formulating the product, or a formulated composition containing the compound A is provided.

In another embodiment of the invention, a method of formulating compound A or a formulation comprising compound A that utilizes the tendency of the zwitterionic solubilizer to bind hydrogen via intermolecular interaction with a drug compound. A method or composition is provided in which the zwitterionic solubilizer is preferably aspartic acid, preferably D-aspartic acid, preferably L-aspartic acid.

Intended Equivalents As used herein, compound A can be in free or unsalted form. The salt of compound A, preferably the pharmaceutically acceptable salt of compound A, preferably the non-hygroscopic, pharmaceutically acceptable salt of compound A is intended to work similar to the formulations of the present invention. Will be done. As such, the salt of compound A, preferably the pharmaceutically acceptable salt of compound A, is intended to be the equivalent in the formulations of the present invention.

The pH of the aqueous formulation of the present invention is preferably a small amount of an organic or inorganic acid other than aspartic acid, acetic acid, glutamic acid, lactic acid or glucuronic acid, or a base such as ammonium hydroxide, monoethanolamine, ethylenediamine, tromethamine, triethanolamine. It is intended that the addition of sodium hydroxide will be adjusted between 2 and 4 without altering the uniformity of the formulation or the properties of the invention.

Without further detail, one of ordinary skill in the art will be able to take full advantage of the invention using the preceding description. The following examples are therefore construed as merely exemplary and do not limit the scope of the invention in any way.

Compound A as a free base was tested with various solubilizers to see if a suitable agonist could be identified as solubilizing the compound in water.

[Examples 1 to 6]
Solubility screening
(Maximum 5 mg / mL at room temperature)
Solubility of compound A was performed by adding a known amount of drug to a particular amount of aqueous medium and then stirring for 24 hours at room temperature (RT). The results are shown below.

Table 1 shows the solubility of compound A in different aqueous media, with a target solubility of up to 5 mg / mL. 300 mM phosphoric acid and 115.7 mM maleic acid medium were unable to solubilize 1 mg / mL of compound A. 50 mM citric acid showed a solubility of <2 mg / mL. 9.5 mM lactic acid, 170 mM acetic acid and 72.8 mM methanesulfonic acid showed a solubility of> 3.5 mg / mL.

[Examples 7 to 13]
Solubility screening
(Maximum 2 mg / mL at room temperature)

Table 2 shows the solubility of compound A in different aqueous media, with a target solubility of up to 2 mg / mL. 10 mM hydrochloric acid and 25 mM tartaric acid medium were unable to solubilize 1 mg / mL of compound A. 10 mM acetic acid, 10 mM methanesulfonic acid, 25 mM lactic acid, 25 mM citric acid, and 25 mM aspartic acid showed a solubility of> 1 mg / mL. The above data surprisingly show that there is no correlation between the acid solubilizer pKa and the solubility of compound A.

Acetic acid, citric acid and aspartic acid were further investigated in Example 14.

[Example 14]

As shown in the solubility data in Table 3, the order of counterions for solubility enhancement is L-aspartic acid> acetic acid> citric acid. At pH 4.0, none of the counterions showed a solubility of> 0.5 mg / mL. L-aspartic acid produced the highest solubility in the pH range of 3 to 3.5. Surprisingly, only acetic acid and L-aspartic acid showed sufficient solubility in pH range 3.

[Example 15]
The water solubility of Compound A with glutamic acid and glucuronic acid was investigated in Example 15. The results are reported in Table 4.

Overview of Solubility Screening from Examples 1-15 Inorganic and organic solubilizers were screened for their ability to promote the solubility of Compound A in water. Counterions derived from inorganic acids such as hydrochloric acid and phosphoric acid did not result in sufficient solubility enhancement compared to organic counterions. The organic solubilizers tested were methanesulfonic acid, acetic acid, citric acid, lactic acid, tartaric acid, maleic acid and aspartic acid. The additional organic solubilizers tested were glutamic acid and glucuronic acid.

This data surprisingly demonstrated that solubility is not only a function of pH, but also depends on the nature of the acid counterion. The equilibrium solubility data in Table 3 showed that aspartic acid and acetic acid provided significantly better solubility at pH 3. Aspartic acid was found to provide the highest solubility of 4 mg / mL at pH <3.

[Example 16]
The solubility of compound A was determined separately in Example 16 by adjusting the molar ratio of L-aspartic acid to the drug. The drug and counterion concentrations were measured in the supernatant and the Ksp (solubility product) was calculated (Table 5).

The Ksp measurements in Table 5 indicate that the pH max for compound A is (3.5-3.6) in L-aspartic acid. Formulations between pH 3.0 and 3.5 provide a safe margin for any pH shift while maintaining the pH close to the generally acceptable pH range (4-9) for injections.

[Example 17]
Injection-site reaction In-vivo studies were performed on cynomolgus monkeys and administered IV doses of 30 mM L-aspartic acid and 3.7% mannitol, compound A in a vehicle at a pH of approximately 3.0 in sterile water for injection. For these tests, compound A was used in the form of non-stoichiometric hydrate according to Table 6.

Surprisingly, no compound A-related injection site reaction was observed in monkeys after saline lavage following weekly IV bolus dosing of Compound A into the elbow midline vein. These results support the conclusion that the IV formulation containing compound A and aspartic acid at approximately pH 3 was safe for human IV administration.

Although preferred embodiments of the invention are exemplified above, the invention is not limited to the detailed description disclosed herein, but all modifications within the scope of the following claims. It will be understood that the right to is preserved.

Claims (34)

a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers;
c) A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid, and optionally
d) A pharmaceutical product containing water. The pharmaceutical formulation according to claim 1, wherein the amount of aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid or glucuronic acid is effective in providing a pH between about 2 and about 4. The pharmaceutical formulation according to claim 1 or 2, wherein the amount of aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid or glucuronic acid is effective in producing a pH between about 2.7 and about 3.6. The pharmaceutical according to any one of claims 1 to 3, wherein the amount of aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid or glucuronic acid is effective in producing a pH between about 2.9 and about 3.5. pharmaceutical formulation. The pharmaceutical according to any one of claims 1 to 4, wherein the amount of aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid or glucuronic acid is effective in producing a pH between about 3.0 and about 3.5. pharmaceutical formulation. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the molar ratio of compound A: solubilizer is selected from about 1: 1 to 1: 125. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the molar ratio of compound A: solubilizer is selected from about 1: 1 to 1:30. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the molar ratio of compound A: solubilizer is selected from about 1: 1 to 1: 100. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the molar ratio of compound A: solubilizer is selected from about 1:10 to 1:30. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the solubilizing acid is in an amount of about 0.5 mg to about 10 mg per 1.0 mg of Compound A. The pharmaceutical preparation according to any one of claims 1 to 10, wherein the solubilizer is aspartic acid. The pharmaceutical preparation according to any one of claims 1 to 11, wherein the filler or the combination of the fillers is an effective amount for forming a dry powder or a freeze-dried powder or a cake. The pharmaceutical preparation according to any one of claims 1 to 11, wherein the filler or the combination of the fillers is in an amount of about 20 mg to about 200 mg per 1.0 mg of Compound A. The fillers are mannitol, mannose, melibiose, octulose, fructose, lactose, sucrose, trehalose, sorbitol, glucose, galactose, glycine, dextrose, raffinose, ribose, xylitol, xylose, cyclodextrin, dextran, cellulose, povidone, PEG300, The pharmaceutical preparation according to any one of claims 1 to 11, which comprises PEG400, PEG3350, PEG6000, PEG8000, polygalacturonic acid, galacturonic acid, lysine, arginine, glycine or galactose or a combination thereof. The pharmaceutical preparation according to any one of claims 1 to 14, wherein the filler is essentially mannitol. The pharmaceutical preparation according to any one of claims 1 to 15, which comprises about 0.1 mg to about 4 mg of compound A. The pharmaceutical preparation according to any one of claims 1 to 15, which comprises about 0.5 mg to about 1.5 mg of Compound A. The pharmaceutical preparation according to any one of claims 1 to 17, which does not contain water. The pharmaceutical preparation according to any one of claims 1 to 17, which contains water. The pharmaceutical preparation according to any one of claims 1 to 19, wherein the compound A is in the form of a free base. Construction

Compound A with
Or its tautomer,
Or a method for producing a pharmaceutical product containing a pharmaceutically acceptable salt thereof.
a)
i) At least one solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid;
ii) Compound A or its tautomer or pharmaceutically acceptable salt whose pH is maintained between about 3.0 and 3.5;
iii) Filler or combination of fillers; and
Iv) Steps to form a solution containing water;
b) Optionally filter the solution;
c) Optionally fill a lyophilized vial with the filtered solution and freeze at about -45 ° C; as well.
d) A method comprising the steps of freeze-drying the frozen solution or evaporating the unfrozen solution. a) The filler is in an amount of about 20 mg to about 200 mg of mannitol;
b) The solubilizer is about 0.5-3.0 mg of L-aspartic acid;
c) The method of claim 21, wherein the amount of compound A or its tautomer or pharmaceutically acceptable salt is selected from about 0.1 mg to about 2 mg. a) The solution is filtered and filled into lyophilized vials;
b) Freeze the solution at about -45 ° C;
c) The method of claim 21 or 22, wherein the frozen solution is freeze-dried. It is a method of manufacturing pharmaceutical products.
1)
a) Structure

A pharmaceutically effective amount of compound A, which has
Or its tautomer,
Or its pharmaceutically acceptable salt;
b) Filler or combination of fillers;
c) A solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid; and
d) Steps to combine water into a mixture;
2) A method comprising the steps of optionally evaporating or lyophilizing the mixture to form a powder or cake. Construction

Compound A with
Or its tautomer,
Or a method for producing a pharmaceutical product containing a pharmaceutically acceptable salt thereof.
a)
i) At least one solubilizer selected from aspartic acid, acetic acid, glutamic acid, methanesulfonic acid, lactic acid and glucuronic acid;
ii) Compound A or its tautomer or pharmaceutically acceptable salt whose pH is maintained between about 3.0 and 3.5;
iii) Filler or combination of fillers; and
Iv) Steps to form a solution containing water;
b) Optionally filter the solution;
c) Optionally fill a lyophilized vial with the filtered solution and freeze at about -45 ° C;
d) Freeze-dry the frozen solution or evaporate the unfrozen solution;
(e) A method comprising adding water to form an injectable solution. A pharmaceutical product prepared by the method according to any one of claims 21 to 25. A method of treating a disease in which regulation of STING (interferon gene stimulator) is beneficial in a patient in need of treatment, wherein the patient is treated with about 0.1 mg / mL to about 2 mg / mL of Compound A, about 20 mg. Includes the step of intravenously administering an effective amount of the formulation as defined in claim 1, comprising mannitol in an amount of / mL to about 200 mg / mL, aspartic acid in an amount of about 0.5 to 3.0 mg / mL, and water. ,Method. The diseases for which regulation of STING is beneficial are inflammation, allergies and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, dermatitis, polysclerosis, humans. 28. The method of claim 27, selected from immunodeficiency virus (HIV) infection, AIDS, cancer and precancerous syndrome. A method for treating a disease in which regulation of STING (interferon gene stimulating factor) is beneficial in a patient in need of treatment, wherein the pharmaceutical preparation according to any one of claims 1 to 20 is used for the patient. A method comprising the step of intravenously administering an effective amount. The diseases for which regulation of STING is beneficial are inflammation, allergies and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, dermatitis, polysclerosis, humans. 29. The method of claim 29, selected from immunodeficiency virus (HIV) infection, AIDS, cancer and precancerous syndrome. The pharmaceutical preparation according to any one of claims 1 to 20, for use in the treatment of a disease in which regulation of STING (interferon gene stimulator) is beneficial. The diseases for which regulation of STING is beneficial are inflammation, allergies and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, skin irritations, polysclerosis, humans. The pharmaceutical formulation according to claim 31, which is selected from immunodeficiency virus (HIV) infection, AIDS, cancer and precancerous syndrome. Use of the pharmaceutical preparation according to any one of claims 1 to 20 for the treatment of a disease in which regulation of STING (interferon gene stimulator) is beneficial. The diseases for which regulation of STING is beneficial are inflammation, allergies and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, dermatitis, polysclerosis, humans. The use according to claim 33, which is selected from immunodeficiency virus (HIV) infection, AIDS, cancer and precancerous syndrome.